Myeloma and DNA damage

Abstract

DNA damaging agents have represented the first effective treatment for the blood cancer multiple myeloma, and after 65 years since their introduction in the clinic, they remain one of the mainstay therapies for this disease. Myeloma is a cancer of plasma cells. Despite exceedingly slow proliferation, myeloma cells present extended genomic rearrangements and intense genomic instability, starting at the premalignant stage of the disease. Where does such DNA damage stem from? A reliable model argues that the powerful oncogenes activated in myeloma as well the phenotypic peculiarities of cancer plasma cells, including the dependency on the proteasome for survival and the constant presence of oxidative stress, all converge on modulating DNA damage and repair. Beleaguered by these contraposing forces, myeloma cells survive in an precarious balance, where the robust engagement of DNA repair mechanisms to guarantee cell survival is continuously challenged by rampant genomic instability, essential for cancer cells to withstand hostile selective pressures. Shattering this delicate equilibrium has been the goal of the extensive use of DNA damaging agents since their introduction in the clinic, now enriched by novel approaches, that leverage upon synthetic lethality paradigms. Exploiting the impairment of homologous recombination caused by myeloma genetic lesions or treatments, it is now possible to design therapeutic combinations which could target more effectively myeloma cells. Furthermore, DNA damaging agents, as demonstrated in solid tumors, may sensitize cells to immune therapies. In all, targeting DNA damage and repair remains as central as ever in myeloma, also for the foreseeable future.